University of Oulu

Anastasopoulou, S., Nielsen, R. L., Als-Nielsen, B., Banerjee, J., Eriksson, M. A., Helenius, M., Heyman, M. M., Johannsdottir, I. M., Jonsson, O. G., MacGregor, S., Mateos, M. K., Mayoh, C., Mikkel, S., Myrberg, I. H., Niinimäki, R., Schmiegelow, K., Taskinen, M., Vaitkeviciene, G., Warnqvist, A., … Ranta, S. (2022). Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: Phenotypes, risk factors and genotypes. Haematologica, 107(10), 2318–2328.

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia : phenotypes, risk factors and genotypes

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Author: Anastasopoulou, Stavroula1,2; Bodil Als-NielsenNielsen, Rikke Linnemann3,4; Als-Nielsen, Bodil3;
Organizations: 1Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
2Childhood Cancer Research Unit, Department of Women's and Children's Health; Karolinska Institutet, Stockholm, Sweden
3Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
4Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark
5Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki, Finland
6Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
7Department of Pediatric Hematology/Oncology, Oslo University Hospital, Oslo, Norway
8Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland
9QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
10Kids Cancer Centre, Sydney Children’s Hospital Randwick, Sydney, New South Wales, Australia
11Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
12Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia
13Department of Hematology and Oncology, University of Tartu, Tartu, Estonia
14Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
15Department of Children and Adolescents, Oulu University Hospital and University of Oulu, PEDEGO Research Unit, Oulu, Finland
16Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
17Children’s Hospital, affiliate of Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius, Lithuania
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.6 MB)
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Language: English
Published: Ferrata Storti Foundation, 2022
Publish Date: 2023-06-30


Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

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Series: Haematologica
ISSN: 0390-6078
ISSN-E: 1592-8721
ISSN-L: 0390-6078
Volume: 107
Issue: 10
Pages: 2318 - 2328
DOI: 10.3324/haematol.2021.280016
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3123 Gynaecology and paediatrics
Funding: This work was supported by the Swedish Childhood Cancer Fund (grants KP2017-0010, TJ2020-0082, TJ2019-0031), Stockholm county, the Danish Childhood Cancer Foundation (TRAVERSE, 2018-3755) and the Interregional Childhood Oncology Precision Medicine Exploration (iCOPE), a cross-Oresund collaboration between University Hospital Copenhagen, Rigshospitalet, Lund University, Region Skåne and Technical University Denmark (DTU), supported by the European Regional Development Fund. This work was part of Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by the Danish CancerSociety (R-257-A14720) and the Danish Childhood Cancer Foundation (2019-5934). This work was also supported by a Cancer Institute NSW Fellowship (grant ECF181430).
Copyright information: © 2022 Ferrata Storti Foundation. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.